The proposed program Is a rationally designed program to study the synthesis, chemistry, potential synthesis applications, and biological importance of quinone methides. A series of studies expanding the work on quinone methide initiated cyclization reactions is proposed. In addition, the intermolecular reaction of quinone methides and benzyl cations with a series of one, two and three carbon 'units' (ylides, alkenes, allenes and 1,3-dipoles) will be explored. The scope, limitations, and synthetic utility of these reactions will be investigated. The synthesis of neolignans via an isolated quinone methide and a semiquinone methide will also be studied. The anthracycline antitumor antibiotics, adriamycin, daunomycin, and menogaril show potent clinical antitumor properties, and are among the most widely used chemotherapeutic agents in the fight against cancer. In spite of this, we still do not understand much of the basic chemistry of these compounds. Several research groups have provided unequivocal evidence for the intermediacy of quinone methides in the chemistry of several anthracycline antitumor antibodies. However, there is conflicting evidence as to whether these intermediates are responsible for the antitumor activity, or, simply provide a mechanism for the observed cytotoxicity of the compounds. Due to the instability of the quinone methides derived from the anthracyclines, studies on the chemistry of these intermediates have produced inconclusive results. The proposed research is designed to study the chemistry of the anthracyclines and the role quinone methides may play in their biological activity. We propose to synthesize, characterize and study the chemistry of a series of model quinone methides. The experience gained in simple tricyclic systems will be the basis for studies on tetracyclic compounds, structurally quite similar to the anthracycline antibiotics, but lacking unnecessary complication functionality. The chemistry of the quinone methides will be thoroughly investigated, including a study of their reaction with nucleosides and nucleotides. Even if quinone methides are only responsible for the undesired cytotoxic properties of the anthracyclines, a thorough understanding of the factors affecting their formation, stability and chemistry, particularly with biological nucleophiles such as nucleic acids and proteins is extremely important. Should quinone methides prove to be responsible for all or part of the antitumor properties, an even better reason exists for studying their synthesis and chemistry. The chemistry of semiquinone methides which are possible, but perhaps unlikely, intermediates responsible for the antitumor / cytotoxic properties will also be explored.